rs1800014

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000311.5(PRNP):c.655G>A(p.Glu219Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.004 in 1,613,590 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 18 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 180 hom. )

Consequence

PRNP
NM_000311.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: 1.04

Publications

105 publications found

Variant links:

Genes affected

PRNP (HGNC:9449): (prion protein (Kanno blood group)) The protein encoded by this gene is a membrane glycosylphosphatidylinositol-anchored glycoprotein that tends to aggregate into rod-like structures. The encoded protein contains a highly unstable region of five tandem octapeptide repeats. This gene is found on chromosome 20, approximately 20 kbp upstream of a gene which encodes a biochemically and structurally similar protein to the one encoded by this gene. Mutations in the repeat region as well as elsewhere in this gene have been associated with Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Straussler disease, Huntington disease-like 1, and kuru. An overlapping open reading frame has been found for this gene that encodes a smaller, structurally unrelated protein, AltPrp. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

PRNP Gene-Disease associations (from GenCC):

Gerstmann-Straussler-Scheinker syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
Huntington disease-like 1
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
inherited Creutzfeldt-Jakob disease
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
familial Alzheimer-like prion disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
fatal familial insomnia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
PrP systemic amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PRNP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000311.5

BP4

Computational evidence support a benign effect (MetaRNN=0.00404042).

BP6

Variant 20-4699875-G-A is Benign according to our data. Variant chr20-4699875-G-A is described in ClinVar as Benign. ClinVar VariationId is 13409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00308 (468/151736) while in subpopulation SAS AF = 0.0552 (264/4786). AF 95% confidence interval is 0.0497. There are 18 homozygotes in GnomAd4. There are 311 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 468 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRNP	NM_000311.5 link	c.655G>A	p.Glu219Lys	missense_variant	Exon 2 of 2	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRNP	ENST00000379440.9 link	c.655G>A	p.Glu219Lys	missense_variant	Exon 2 of 2	1	NM_000311.5	ENSP00000368752.4	P04156-1
PRNP	ENST00000424424.2 link	c.655G>A	p.Glu219Lys	missense_variant	Exon 2 of 2	1		ENSP00000411599.2	P04156-1A2A2V1
PRNP	ENST00000430350.2 link	c.655G>A	p.Glu219Lys	missense_variant	Exon 2 of 2	1		ENSP00000399376.2	P04156-1
PRNP	ENST00000457586.2 link	c.655G>A	p.Glu219Lys	missense_variant	Exon 2 of 2	1		ENSP00000415284.2	P04156-1X6RKS3

Frequencies

GnomAD3 genomes

AF:

0.00309

AC:

468

AN:

151618

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000291

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000526

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0332

Gnomad SAS

AF:

0.0553

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00802

AC:

2016

AN:

251398

AF XY:

0.00934

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0356

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00410

AC:

5987

AN:

1461854

Hom.:

180

Cov.:

AF XY:

0.00515

AC XY:

3745

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.00132

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0500

AC:

1986

AN:

39700

South Asian (SAS)

AF:

0.0415

AC:

3581

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000656

AC:

AN:

1111978

Other (OTH)

AF:

0.00457

AC:

276

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

428

855

1283

1710

2138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00308

AC:

468

AN:

151736

Hom.:

Cov.:

AF XY:

0.00420

AC XY:

311

AN XY:

74124

show subpopulations

African (AFR)

AF:

0.000290

AC:

AN:

41334

American (AMR)

AF:

0.000526

AC:

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0330

AC:

169

AN:

5114

South Asian (SAS)

AF:

0.0552

AC:

264

AN:

4786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10534

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67964

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00196

Hom.:

Bravo

AF:

0.00211

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00875

AC:

1062

Asia WGS

AF:

0.0450

AC:

155

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 05, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Reclassified - variant of unknown significance

Uncertain:1

Feb 01, 2012

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inherited prion disease

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Huntington disease-like 1

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.82

.;T;T

MetaRNN

Benign

0.0040

T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.0

N;N;.

PhyloP100

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

0.0

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.035

D;D;D

Sift4G

Benign

0.090

T;T;T

Polyphen

0.0050

B;B;.

Vest4

0.17

MVP

1.0

MPC

0.55

ClinPred

0.0090

GERP RS

3.1

Varity_R

0.21

gMVP

0.86

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over